CD138, which acts as a receptor for the extracellular matrix, is overexpressed on multiple myeloma (MM) cells and has been shown to influence MM cell development and/or proliferation. CD138 is also expressed on cells of ovarian carcinoma, cervical cancer (Numa et al., 2002), endometrial cancer (Choi et al., 2007), kidney carcinoma, gall bladder, transitional cell bladder carcinoma, gastric cancer (Wiksten et al. 2008), prostate adenocarcinoma (Zellweger et al., 2003), mammary carcinoma (Loussouarn et al., 2008), non small cell lung carcinoma (Shah et al., 2004), squamous cell lung carcinoma (Toyoshima et al., 2001), colon carcinoma cells and cells of Hodgkin's and non-Hodgkin's lymphomas, colorectal carcinoma (Hashimoto et al., 2008), hepato-carcinoma (Li et al., 2005), chronic lymphocytic leukemia (CLL), pancreatic (Conejo et al., 2000), and head and neck carcinoma (Anttonen et al., 1999) to name just a few.
The publications and other materials, including patents, used herein to illustrate the invention and, in particular, to provide additional details respecting the practice are incorporated herein by reference. For convenience, the publications are referenced in the following text by author and date and/or are listed alphabetically by author in the appended bibliography.
Tassone et al. (2004) reported excellent binding of the murine IgG1 antibody B-B4 to the CD138 antigen expressed on the surface of MM cells. Tassone also reported high cytotoxic activity of the immunoconjugate B-B4-DM1, which comprises the maytansinoid DM1 as an effector molecule, against multiple myeloma cells (see also US Patent Publ. 20070183971).
Ikeda et al. (2008 and 2009) reported promising in vitro results and results in xenograft models with the immunoconjugate BT062, which is based on B-B4.
While Tassone et al. and Ikeda et al. represent contributions to providing an effective treatment of MM and a composition of matter that may be employed in such a treatment, there remain a number of needs in the art.
While the use of immunoconjugates, in particular those which have highly toxic effector molecules which are functionally attached to a targeting agent that binds to, e.g., antigens that are not only expressed on target cells, such as tumor cells, but also on non-target cells which perform vital functions in the organism, have been shown to be effective in destroying the target cells, many failed due to their toxicity towards non-target cells. In fact, many immunoconjugates have to be discontinued during clinical trials because a balance between effectiveness and toxicity (therapeutic window) could not be found: at concentrations at which the immunoconjugate can confer benefits in terms of combating disease, its toxicity becomes unacceptable. Thus, especially with highly toxic effector molecules, the question often is not only whether the targeting agent of the immunoconjugate can in fact, bring the effector to the target and allow the effector to be released at the target, but also if, on its way to the target cells, the same immunoconjugate will destroy or attack an unacceptable number of cells or organs that are pivotal to the survival of the organism.
US Patent Publication 20110123554 discloses methods and treatment regimens that include the administration of immunoconjugates targeting CD138 to combat diseases, in particular in tolerable amounts. However, while these results showed that the immunoconjugate could be effective, while being tolerable, there is a need for further improved treatment regimens.
There remains in particular a need to provide suitable treatment regimens for diseases associated with CD138 expression, including plasmaproliferative disorders associated with CD138 expression, such as MM. There, more in particular, remains a need for treatment regimens that ensure that toxicities towards non tumor cells, which also express CD138 are kept to a clinically acceptable level, either by employing only certain tolerable amounts of immunoconjugate at levels that balance toxicities with effectiveness to combat diseases and/or by combining the immunoconjugate with cytotoxic agents known to be effective against the disorder in question. There is also a need for treatment regimens that reduce the need for medications that are used to alleviate other symptoms of the disease and for maintenance therapy to maintain a patient's health in a disease-free or limited-disease state after a certain grade of disease control was achieved with the most recent prior treatment.
This invention fulfills, in certain embodiments, one or more of these needs as well as other needs in the art which will become more apparent to the skilled artisan once given the following disclosure.